Improved instrumentation for high-throughput screening of molecular compound libraries has the potential to advance human health by accelerating the drug-discovery process. Current mechanized screening approaches suffer from several drawbacks, including bottlenecks in compound maintenance and disbursement, as well as assay rapidity, accuracy, and content. We propose a microfluidic solution to this problem; we will use a reconfigurable fluidic processor as the basis for a biochemical assay engine to perform screening reactions against libraries of test compounds. Technology developed in our lab currently allows the programmable manipulation of nL-scale droplets of reagents for sample analysis on a 0.4 cm2 reaction surface. We plan to combine these assay capabilities with a molecular library archiving and dispensing system to yield a complete prototype screening platform; stored screening libraries will be dispensed onto the reaction platform from individual capillaries (for small libraries) or from capillary channels in credit-card sized library cartridges (for large libraries). Improvements over existing screening methods will include decreased reagent and compound consumption; decreased platform size, cost, and power usage; and greater instrument reliability due to an almost complete absence of moving parts. The system should be ideal for molecular library screening because it can be easily programmed as needed to perform different sets of assays with an arbitrary number of reaction steps. Furthermore, the compound archiving system will provide a convenient way for researchers to store libraries of test agents in a small format that is robust and can be readily disbursed to various screening centers. The specific aims of this design-driven research are to develop a molecular library archiving and dispensing system; develop a microfluidic assay engine with integrated components for molecular screening; and validation of the performance of the molecular library screening platform using test assays. We plan to collaborate with a molecular assay development lab to demonstrate molecular screening using the prototype platform and have structured our project plan to facilitate this. The goal of this project is to build an assay platform that can be used to screen large libraries of chemical compounds for various biologically-relevant activities. This approach is one of the first steps in identifying candidate therapeutic agents for further research and testing. The assay platform described in this proposal has the potential to accelerate the drug discovery process by enabling more efficient and cost-effective compound screening.